PROJECT SUMMARY In women, reproductive aging is marked by a dramatic decline in ovarian hormone production, and is a time when many women report changes in memory and attention. Animal studies provide powerful evidence that ovarian hormones, in particular 17?-estradiol, play a critical role in shaping the morphology and function of brain regions that are central to higher order cognitive processes and cognitive aging. The degree to which female reproductive aging leads to macrostructural changes in human brain morphology, changes in brain connectivity, and ultimately changes in cognitive functioning represents a significant knowledge gap that has yet to be adequately examined. Ovarian hormone suppression (OHS), a widely used treatment for endometriosis, offers a unique clinical scenario through which to study the impact of estrogen and progesterone changes on the brain and cognition. The treatment allows for the temporary and reversible induction of a postmenopausal-like endocrine status, the effects of which can be observed over the course of a few months, and offers a human analogue of animal studies that have provided substantial evidence for the neuroprotective effects of ovarian hormones and their influence on neural function. In the proposed observational study, we will examine 200 adult women with endometriosis (ages 25 to 40), half of whom will undergo OHS via the gonadotropin releasing hormone (GnRH) antagonist Elagolix, and half of whom will follow a non-hormonal treatment plan, in order to gain critical insights into how the depletion of ovarian hormones impacts the brain and cognition. Women will be examined pre-treatment and at 6 months post-baseline to characterize the progression of changes in response to OHS. In Aim 1, we will characterize the effects of OHS on cognitive functioning. We will employ a comprehensive neuropsychological battery to assess changes in cognition brought on by OHS. In Aim 2, we will utilize state-of-the-field neuroimaging techniques to characterize the impact of OHS on structural brain measures, specifically targeting subfields of the hippocampus, the entorhinal cortex, and white matter pathways using diffusion spectrum imaging. In Aim 3, we will use resting state and task-based fMRI paradigms to determine the effects of OHS on global and regional brain networks. We hypothesize that OHS will impact intrinsic correlations in the default mode, frontoparietal, and limbic networks at rest, and alter prefrontal cortex efficiency during working memory. Finally, in Aim 4, we will test whether polygenic risk for Alzheimer?s disease modifies the effects of OHS on the brain and cognition. The multimodal cognitive neuroscience approach will allows us to model a core aspect of reproductive aging, ovarian hormone depletion, while holding chronological age relatively fixed. This project will clarify the role of ovarian hormones in shaping brain architecture and cognitive functioning, a severely understudied arena in cognitive neuroscience with clear implications for women?s health.